Literatura académica sobre el tema "Bevacizumab, Perfusion CT, angiogenesis, brain tumor"

Tissue perfusion plays a critical role in oncology because growth and migration of cancerous cells require proliferation of new blood vessels through the process of tumor angiogenesis. Computed tomography (CT) perfusion is an emerging functional imaging modality that measures tissue perfusion through dynamic CT scanning following intravenous administration of contrast medium. This noninvasive technique provides a quantitative basis for assessing tumor angiogenesis. CT perfusion has been utilized on a variety of organs including lung, prostate, liver, and brain, with promising results in cancer diagnosis, disease prognostication, prediction, and treatment monitoring. In this paper, we focus on assessing the extent to which CT perfusion characteristics can be used to discriminate liver metastases from neuroendocrine tumors from normal liver tissues. The neuroendocrine liver metastases were analyzed by distributed parameter modeling to yield tissue blood flow (BF), blood volume (BV), mean transit time (MTT), permeability (PS), and hepatic arterial fraction (HAF), for tumor and normal liver. The result reveals the potential of CT perfusion as a tool for constructing biomarkers from features of the hepatic vasculature for guiding cancer detection, prognostication, and treatment selection.

2074 Background: Angiogenesis is a requirement for progression of glioblastoma (GBM) and vascular endothelial growth factor (VEGF) is a mediator of neo-angiogenesis in this tumor. Bevacizumab (Bev), an antibody directed to VEGF, was recently used to treat GBM. However in vivo modifications induced by treatment are still not clearly understood. Aim of this study is to analyze tumor changes induced by Irinotecan (Ir) and Bev, using two different methodologies: relative CBV variation (rCBV) and Difference Perfusion Maps (DPMs). Methods: 42 recurrent GBM patients underwent Bev (10 mg/kg) and Ir (125 or 340 mg/m2) treatment every 2 weeks and were followed up with a radiological protocol, including Dynamic Susceptibility Contrast MRI every 8 weeks. Radiological responses were assessed based on RANO criteria (Wen et al, 2012). Two methods were used to assess perfusion changes. In method A, relative CBV variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. In method B, relative CBV variations with respect to baseline values were calculated into the evolving tumour region by means of a voxel-by-voxel difference. DPMs were created showing where rCBV significantly increased, decreased or remained unchanged. Results: After a median follow-up of 33.5 months median overall survival (OS) was 35.0 weeks and median progression free survival (PFS) was 20.0 weeks. Method A showed a significant decrease of rCBV for patients with stable disease or partial response after 8 weeks of treatment (p = 0.01) while progressing patients maintained elevated levels of rCBV (p = 0.38). Method B, based on DPMs, showed that patients presenting rCBV increase higher than 25° percentile (corresponding to rCBV increase higher than 18% of tumor volume) had a significantly longer PFS (p = 0.045) and OS (p = 0.016). Conclusions: Using DPM we observed that early increase in global perfusion is related to better survival. This may suggest that Bev, when effective, reduces blood-brain barrier permeability with a higher contrast retention in vessels. If confirmed by further studies this measure could be useful in identifying responders to Bev.

OBJECTIVE: To report the serial development of oral mucositis following infusion of bevacizumab in a young woman with a malignant brain tumor and history of cutaneous psoriasis. CASE SUMMARY: A 29-year-old woman with a history of active cutaneous psoriasis and a malignant glioneuronal tumor was treated with bevacizumab for 2.5 years. With each infusion of bevacizumab, she developed oral mucositis within 36 hours. She received temozolomide as part of concurrent therapy with radiation and as maintenance therapy; it was discontinued after continuous therapy for 1.5 years. Bevacizumab 10 mg/kg was added after 7 cycles of maintenance temozolomide, as the tumor had minimal response and evidence of increased perfusion with angiogenesis on imaging studies. All medication, including temozolomide, was evaluated and eventually discontinued, with the exception of bevacizumab, which remained the drug suspected of causing the mucositis. DISCUSSION: Oral mucositis is a frequent adverse effect of cytotoxic chemotherapy, but has not been reported with bevacizumab. The Naranjo probability scale indicated a probable adverse drug reaction. This likely indicates that bevacizumab is one of many drugs known to induce exacerbation of psoriatic disease. We speculate that oral mucositis developed as bevacizumab-induced generation of proinflammatory cytokines within the vascular endothelium, leading to mucosal damage and ulceration. In addition, interruption of reparative angiogenic pathways with bevacizumab likely contributed to the severity of mucositis. CONCLUSIONS: Clinicians should be aware that bevacizumab can potentially exacerbate psoriatic disease.

2030 Background: Dynamic susceptibility contrast-enhanced MRI (DSC MRI) is emerging as an important adjunctive biomarker to assess the effectiveness of anti-angiogenic therapies in the treatment of brain tumors. The purpose of our study is to compare changes in relative cerebral blood volume (rCBV) and in perfusion-permeability index (KTrans) with those of tumor volume measurements (T1c, T2/Flair) in predicting tumor therapeutic response in recurrent high-grade gliomas treated with bevacizumab, an anti-VEGF monoclonal antibody. Methods: 11 patients were treated with one to four cycles of bevacizumab and CPT-11. Their histological diagnoses were: glioblastoma multiforme (n=7), anaplastic astrocytoma (n=2), anaplastic oligodendroglioma (n=1), and diffuse pontine glioma (n=1). All patients had baseline DSC MRI scans prior to the administration of bevacizumab and were followed clinically and radiographically with both conventional and DSC MRI. Mixed model regression was used to compare the pre-treatment and post-treatment levels of each response measure. Results: There were statistically significant reductions in both actual rCBV measurements and T1c enhancement following treatment with bevacizumab and CPT-11. The pretreatment rCBV and T1c rates of change (as determined per 100 days) correlated significantly with time (p values are 0.0229 and 0.0014, respectively), while only the post treatment rCBV demonstrated significant rate of change (p value = 0.0001), suggesting that rCBV may reflect the effects of bevacizumab better than tumor volume. However, when the changes in rate from pre- to post-treatment status were considered, both rCBV and T1c demonstrated significance (p= 0.0001, 0.0157, respectively). There was a trend towards females having higher mean levels of KTrans than males at the same time point relative to treatment onset, but the result was not statistically significant (p=0.072). Conclusions: rCBV as measured from DSC MRI can be used as a surrogate biomarker to determine therapeutic response to bevacizumab. This may influence the neurosurgical risk/benefit equation as well as alter the aggressiveness of the post-operative adjuvant therapy in patients with recurrent gliomas. No significant financial relationships to disclose.

Object Currently, perfusion CT (PCT) is a valuable imaging technique that has been successfully applied to the clinical management of patients with ischemic stroke and aneurysmal subarachnoid hemorrhage (SAH). However, recent literature and the authors' experience have shown that PCT has many more important clinical applications in a variety of neurosurgical conditions. Therefore, the authors share their experiences of its application in various diseases of the cerebrovascular, neurotraumatology, and neurooncology fields and review the pertinent literature regarding expanding PCT applications for neurosurgical conditions, including pitfalls and future developments. Methods A pertinent literature search was conducted of English-language articles describing original research, case series, and case reports from 1990 to 2011 involving PCT and with relevance and applicability to neurosurgical disorders. Results In the cerebrovascular field, PCT is already in use as a diagnostic tool for patients suspected of having an ischemic stroke. Perfusion CT can be used to identify and define the extent of the infarct core and ischemic penumbra core, and thus aid patient selection for acute reperfusion therapy. For patients with aneurysmal SAH, PCT provides assessment of early brain injury, cerebral ischemia, and infarction, in addition to vasospasm. It may also be used to aid case selection for aggressive treatment of patients with poor SAH grade. In terms of oncological applications, PCT can be used as an imaging biomarker to assess angiogenesis and response to antiangiogenetic treatments, differentiate between glioma grades, and distinguish recurrent tumor from radiation necrosis. In the setting of traumatic brain injury, PCT can detect and delineate contusions at an early stage. In patients with mild head injury, PCT results have been shown to correlate with the severity and duration of postconcussion syndrome. In patients with moderate or severe head injury, PCT results have been shown to correlate with patients' functional outcome. Conclusions Perfusion CT provides quantitative and qualitative data that can add diagnostic and prognostic value in a number of neurosurgical disorders, and also help with clinical decision making. With emerging new technical developments in PCT, such as characterization of blood-brain barrier permeability and whole-brain PCT, this technique is expected to provide more and more insight into the pathophysiology of many neurosurgical conditions.

Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain tumor, with a median survival time of only 15 months. Having a clinically applicable genetic biomarker would lead to a paradigm shift in precise diagnosis, personalized therapeutic decisions, and prognostic prediction for GBM. Radiogenomic profiling connecting radiological imaging features with molecular alterations will offer a noninvasive method for genomic studies of GBM. To this end, we analyzed over 3800 glioma and GBM cases across four independent datasets. The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases were employed for RNA-Seq analysis, whereas the Ivy Glioblastoma Atlas Project (Ivy-GAP) and The Cancer Imaging Archive (TCIA) provided clinicopathological data. The Clinical Proteomic Tumor Analysis Consortium Glioblastoma Multiforme (CPTAC-GBM) was used for proteomic analysis. We identified a simple three-gene transcriptome signature—SOCS3, VEGFA, and TEK—that can connect GBM’s overall prognosis with genes’ expression and simultaneously correlate radiographical features of perfusion imaging with SOCS3 expression levels. More importantly, the rampant development of neovascularization in GBM offers a promising target for therapeutic intervention. However, treatment with bevacizumab failed to improve overall survival. We identified SOCS3 expression levels as a potential selection marker for patients who may benefit from early initiation of angiogenesis inhibitors.

3546 Background: VEGFRs and PDGFRs play key roles in the proliferation of HCC and tumor angiogenesis. Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3. This study reports the results of the first European/Asian, open-label, single-agent SU phase II study in pts with unresectable HCC. Methods: Key eligibility criteria include histologically confirmed measurable HCC; ECOG PS =1; Child-Pugh (CP)-A/-B; adequate organ function; and no brain metastases, ascites, or prior liver transplant. Pts receive SU at 50 mg/d for 4 wks every 6 wks (4/2 schedule). The primary endpoint is ORR by RECIST. Other assessments include safety (NCI CTCAE v3.0), PK and antitumor activity (tumor density, volumetric measurement of percent tumor necrosis [VMTN] and intratumor blood perfusion on monthly CT scan). Results: 37 pts (median 61 yrs [range 34–82]; male 92%; PS 0:1, 50%:44%; CP-A/-B, 84%/14%; 40.5% with prior local treatments) received a median of 2 cycles (range 1–7+) of SU. Grade 3–4 toxicities included thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%) and hemorrhage (14%). Grade 1–2 skin toxicity was frequently reported. Dose reductions were required in 27% of pts. Four pts developed grade 5 events including ascites, edema, bleeding, drowsiness and hepatic encephalopathy. Decreased tumor density was observed in 68% of pts and activity assessed by VMTN showed minor (<50%) and major (=50%) post-treatment tumor necrosis in 25% and 46% of pts, respectively. One confirmed PR and 39% SD (best confirmed response) have been achieved. Post-treatment tumor blood perfusion parameters (blood volume and blood flow), decreased by an average of 39% (range: 13–72%). Preliminary PK data do not suggest any differences in drug exposure between risk groups (CP-A or CP-B). Conclusions: Evidence of =50% tumor necrosis in 46% of pts receiving SU suggests outstanding antitumor activity. However, change in tumor size (RECIST) may be inappropriate as a primary endpoint to evaluate SU in patients with HCC. Initial safety findings indicate that further evaluation of SU in this pt population with improved pt selection and dose schedule modification is warranted. [Table: see text]

Abstract: Objective. The aim of this study was to know if quantitative parameters of perfusion CT could predict the response of bevacizumab therapy on patients with brain cancer based on the RECIST.1.1 guidelines Material and methods. This study included 18 patients (11 men and 7 women; mean age, 47,11 years) with brain neoplasm who were undergoing bevacizumab treatment. by comparing baseline studies with the best response achieved after completion of bevacizumab treatment and chemotherapy, patients were divided into two groups according to RECIST (version 1.1) guidelines as follows; responders (CR or PR) and non-responders (SD or PD). CT perfusion parameters (blood flow, blood volume, mean transit time, and permeability) were performed on baseline and were correlated with tumor size at first, then a logistic regression model was used to evaluate predictive factors for a response to bevacizumab treatment. Results. There were early changes shown after only few week of bevacizumab therapy between the 9 responders group of patients and the remaining 9 no responders patients. Then clinical responders showed significantly higher blood flow (P=0.01) than non-responders.Blood flow, accuracy was 80.2% for detection of clinical responders when the cut-off point was set at 50 ml/100 g/min. Patients with high blood flow tumors (≥50 ml/100 g/min) survived significantly longer than those with low blood flow tumors (<50 ml/100 g/min) (p=0.007). Multivariate analysis identified blood flow as a significant independent prognostic factor (p = 0.006; risk ratio, 5.18; 95% IC, 0.48-22.68). Conclusion. This study has shown the possibility that Perfusion CT could predict the response to Bevacizumab treatment in brain tumor